Neurotrophins have long been known to support the survival and differentiation of many neuronal populations through interactions with the trk tyrosine kinase receptors. Recent studies from our laboratory and others have demonstrated that neurotrophins can also elicit cell death via the p75 receptor. Thus, whether a neuron survives or dies in response to neurotrophins may depend on a balance of signaling pathways activated by these different receptors. Although p75 is transiently expressed in many CNS neuronal populations during development, this receptor is not widely expressed in the normal adult brain. However, after damage in the brain expression of p75 can be detected in numerous neurons, suggesting that upregulation of this receptor may be part of an injury or stress response. Since production of NGF is also induced in the brain by many types of damage, we hypothesize that NGF interacts with p75 to eliminate neurons that are compromised by damage. In this grant application we propose to investigate whether the p75 receptor is expressed on dying neurons in vivo as a consequence of pilocarpine-induced seizures. We will compare the number of dying neurons after seizure in normal mice with p75-/- mice to assess the role of this receptor in mediating neuronal loss. These in vivo studies will be accompanied by studies on hippocampal neurons in vitro to investigate the mechanisms of p75-mediated neuronal death. Thus, the goal of these studies is to define the role of the p75 neurotrophin receptor in mediating cell death in hippocampal neurons, particularly under conditions of brain injury.